Neurokinin A (NKA) is part of a group of neuropeptides known as tachykinins or neurokinins, which includes substance P (SP) and neurokinin B (NKB). The biological effects of neurokinin A and of the other tachykinins are mediated by specific receptors of the family of protein-G-coupled transmembrane 7-domain receptors known as NK1, NK2 and NK3. The tachykinin receptor NK2 binds neurokinin A, while the receptors NK1 and NK3 bind, respectively, substance P and neurokinin B see for example, Pennefather J. N. et al., Life Sci., 2004, 74, 1445-1463. The tachykinin receptors NK2 are very widely expressed in the peripheral nervous system where they mediate the wide variety of effects produced by neurokinin A, especially, and in a non-limiting manner, in the respiratory system (bronchoconstriction, coughing, inflammation, bronchial hyperactivity, etc.) (Joos G. F., Hand. Exp. Pharm., 2004, 164, 491-510; Advenier C. et al., Eur. Respir. J., 1997, 10, 1892-1906), the gastrointestinal system (inflammation, infection, motility, pain, etc.) (Holzer P. Hand. Exp. Pharm., 2004, 164, 511-55) and the urinary system (vesical hyperactivity, inflammation, infection, etc.) (Kiss S. et al., Neurosci. Lettrs., 2001, 313, 57-60; Warner F. J. et al., Eur. J. Pharmacol., 2002, 438, 171-177). The tachykinin receptor NK2 is also expressed in the brain (Hagan R. M. et al., Regul. Pept., 1993, 46, 9-19; Steinberg R., et al., Eur. J. Neurosci., 1998, 10, 2337-2345; Bensaid M., et al., Neurosci. Lett., 2001, 303, 25-28; Saffroy M. et al., J. Neurochem., 2001, 79, 985-996; Saffroy M. et al., Neuroscience, 2003, 116, 761-773) and the spinal column (Yashpal K. et al., Brain Res., 1990, 506, 59-266), where it mediates the central effects of neurokinin A.
By way of example, experimental data shows that blocking the tachykinin receptor NK2 with an antagonist may be a treatment for major depression (Emonds-Alt, Handb Exp. Pharm., 2004, 219-244) and also functional and painful gastrointestinal disorders such as irritable bowel syndrome (IBS) (Emonds-Alt, Handb Exp. Pharm., 2004, 219-244; Lecci A. et al., Br. J. Pharmacol., 2004, 141, 1249-1263).
Many prior art patents or patent applications describe compounds that exhibit a proclivity for binding to the tachykinin receptors. For example, international patent application WO 96/23787 discloses compounds of formula A:
in which, especially:                A may represent the divalent radical —O—CH2—CO—;        Am, m, Ar1 and T have different values.        
The compounds (A) show affinity for the tachykinin receptors NK1, NK2 or NK3 in general.
Patent application EP-A-0 776 893 concerns compounds of formula B:
in which, especially:                D-E may represent a divalent radical —O—CH2—CH2—;        L, G, E, A, B, Ra and Rb have different values.        
The compounds (B) are antagonists of both tachykinin receptors NK1 and NK2.
Patent application WO 00/34274 teaches and claims cyclohexylpiperidine derivatives that are antagonists of both the substance P receptors NK1 and the neurokinin A receptors NK2.
Patent application WO 02/094821 discloses morpholine derivatives that are antagonists of both human tachykinin receptors NK2 and NK3.
The novel compounds of the present invention show a very strong affinity for the human neurokinin A receptors NK2 and are antagonists of said receptors.
Furthermore, the compounds according to the present invention show good bioavailability when they are administered orally and subsequently cross the blood-brain barrier.